Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer.
Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer.
复制标题
Siglec15塑造非炎症性肿瘤微环境并预测膀胱癌的分子亚型
作者：
Hu J;Yu A;Othmane B;Qiu D;Li H;Li C;Liu P;Ren W;Chen M;Gong G;Guo X;Zhang H;Chen J;Zu X
原理：唾液酸结合免疫球蛋白样凝集素15（Siglec15）是癌症免疫正常化治疗的一个新兴靶点。然而，泛癌抗Siglec15治疗尚未得到验证，且Siglec15在膀胱癌（BLCA）中的潜在作用仍不明确。
方法：我们基于从癌症基因组图谱获得的RNA测序数据，通过泛癌分析全面评估了Siglec15的表达模式和免疫学作用。然后，我们系统地将Siglec15与膀胱癌肿瘤微环境（TME）中的免疫学特征相关联，包括免疫调节剂、癌症免疫周期、肿瘤浸润免疫细胞（TIICs）、免疫检查点和T细胞炎症评分。我们还分析了Siglec15在预测膀胱癌分子亚型以及对几种治疗方案的反应中的作用。我们的结果在多个公共队列以及我们的膀胱癌肿瘤微阵列队列（湘雅队列）中得到了验证。我们开发了一种免疫风险评分（IRS），对其进行了验证，并测试了它预测预后和对癌症免疫治疗反应的能力。
结果：我们发现Siglec15在多种癌症的肿瘤微环境中特异性高表达。基于Siglec15与免疫调节剂、肿瘤浸润免疫细胞、癌症免疫周期、免疫检查点和T细胞炎症评分呈负相关的证据，我们假设Siglec15在膀胱癌中构建了一个非炎症性肿瘤微环境。Siglec15高表达的膀胱癌对癌症免疫治疗不敏感，但出现疾病超进展的发生率更高。Siglec15高水平表明膀胱癌为管腔亚型，其特征为免疫浸润较低，对癌症免疫治疗和新辅助化疗的反应较低，但对抗血管生成治疗以及诸如阻断Siglec15、β -连环蛋白、过氧化物酶体增殖物激活受体 - γ和成纤维细胞生长因子受体3通路等靶向治疗的反应较高。值得注意的是，抗Siglec15与癌症免疫治疗联合可能是一种比单一治疗更有效的策略。免疫风险评分能够准确预测预后和对癌症免疫治疗的反应。
结论：抗Siglec15免疫治疗可能适用于膀胱癌治疗，因为Siglec15与膀胱癌中的非炎症性肿瘤微环境相关。Siglec15还可预测分子亚型以及对几种治疗方案的反应。
Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.
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DOI：
10.1158/1078-0432.ccr-16-3133
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
4.6
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
通讯作者：
Roychowdhury S
影响因子：
4.3
作者：
Angata, Takashi;Tabuchi, Yukako;Nakamura, Mitsuru
通讯作者：
Nakamura, Mitsuru
影响因子：
23.4
作者：
Groenendijk, Floris H.;de Jong, Jeroen;van der Heijden, Michiel S.
通讯作者：
van der Heijden, Michiel S.
影响因子：
12.3
作者：
Li B;Severson E;Pignon JC;Zhao H;Li T;Novak J;Jiang P;Shen H;Aster JC;Rodig S;Signoretti S;Liu JS;Liu XS
通讯作者：
Liu XS